Phase III Trial Results of Corifollitropin Alfa

Published in Fertility Matters Issue 9, Page 2 
Phase III results from clinical trials of corifollitropin alfa, the first sustained follicle stimulant, were presented by Dr. Robert Boostanfar from HRC Fertility.

Corifollitropin alfa, he said, has been developed for controlled ovarian stimulation for multiple follicles and pregnancy in women undergoing ART. The goals of the development program, he added, were a more simple treatment regimen characterized by fewer injections, a reduced likelihood of errors during drug administration and greater convenience for the patient.

The key to the realization of these aims lies in the half-life of corifollitropin; earlier studies had shown that a single injection could replace the first seven daily injections of FSH. However, these earlier dose-finding studies had also shown that dose selection was somewhat dependent on patient body weight, the optimal dose for a one-week interval lying between 60 and 180 micrograms.

Computer modeling indicated that two therapeutic strengths of corifollitropin alfa would be most appropriate and guarantee equal exposure - 100 micrograms for patients with a body weight of 60 kg or less, and 150 micrograms for those weighing more than 60 kg. The same studies also showed that a daily recombinant FSH (Follistim) dose of 150 IU from day 8 onwards (at the end of the corifollitropin alfa phase) would be sufficient to reach the criterion for hCG (at least three follicles >17 mm).

The phase III trial, known as "ENGAGE", was a double-blind, single cycle randomized trial in 1509 patients recruited in 34 North American and European fertility clinics, with a primary endpoint of ongoing pregnancy rate, and was, said Dr Boostanfar, the largest randomized trial ever performed in IVF and ICSI.

In the trial patients were randomized to receive a single 150 microgram injection of corifollitropin alfa or a 200 IU daily dose of recombinant FSH for seven days, followed by a daily dose of Follistim from day 8 as required. Starting on day 5 of stimulation, all patients received 0.25 mg/day ganirelix until final oocyte maturation was induced by hCG. Results showed that the median duration of stimulation needed to reach the criteria for hCG was exactly the same for both groups, just nine days; this broke down as a single injection of corifollitropin alfa followed by just two days Follistim in the treatment group, and nine daily injections of Follistim in the control group.

However, it was found that one-third of patients in the corifollitropin alfa group reached the criterion for hCG with the single injection and without any daily FSH addition. The mean number of oocytes retrieved from each group was clinically equivalent (13.7 vs 12.5) but the estimated difference in the number retrieved from both groups (1.2 oocytes more in the corifollitropin alfa group) was statistically significant.

As expected, age had a predictable effect on oocyte retrieval, with both the treatment and control groups showing a progressively declining number retrieved with age - but with always slightly more retrieved in the corifollitropin alfa group. The proportion of MII oocytes available for ICSI was comparable (78.9 vs 77.4 percent). Also as expected from the pattern of oocyte retrieval, more cleavage stage embryos were available for transfer at day 3 in the corifollitropin alfa group (8.3 vs 7.4), with slightly more of good quality (4.6 vs 4.4).

Because the trial set a limit of two embryos transferred in each cycle, the mean number of embryos transferred was identical for each group (1.7). These transfers yielded an ongoing pregnancy rate of 38.9 percent per started cycle in the corifollitropin alfa group, and 38.1 percent in the reference Follistim group. Rates per embryo transfer were slightly higher.

The number of subjects with OHSS was similar in both groups, totaling for all grades 7.0 percent in the corifollitropin group (including 1.9 percent hospitalizations), and 6.3 percent in the Follistim group (1.2 percent hospitalizations). Thus, having for the first time announced the ENGAGE study results in the USA, Dr Boostanfar concluded that ART treatment with corifollitropin alfa combined with a GnRH antagonist results in: